1. Field of the Discovery
Presently described are methods for the identification and treatment of invasive and/or metastatic cancers, e.g., breast cancer. In particular, the description provides methods of diagnosing a metastatic cancer, e.g., metastatic breast cancer, or assessing the risk of developing the same by detecting the amount of Lamellipodin (Lpd) protein or Lpd gene expression or both in a subject.
2. Background Information
Cancer cell invasion is a hallmark of metastasis, and remains a significant health problem and complicate the decisions regarding therapy for cancer sufferers. In particular, breast cancer metastasis is one of the leading causes of cancer-associated mortality in women worldwide. Metastatic breast cancer is also classified as Stage 4 breast cancer that spreads to lungs, liver, bones or other parts of the body. Cancer cell metastasis requires modulation of protein regulators of cellular mobility, including actin filaments and associated cytoskeletal regulators. The mesenchymal mode of cancer cell invasion is mediated by elongated membrane protrusions driven by the assembly of branched F-actin networks. How deregulation of actin regulators promotes cancer cell invasion is still enigmatic.
The lamellipodium is the protrusion of a cell enabling the cell to migrate and is driven by the polymerization of a cytoskeletal protein, actin, at the leading edge of the cell. It contains a three-dimensional actin mesh, which pushes the membrane forward. The protrusion of the lamellipodium is coupled to the attachment of the cell to the substratum directly behind the leading edge. Finally, the turnover of adhesions at the rear of the cell allows the cell to translocate. Thus, the lamellipodium is pivotal for efficient mesenchymal cell migration and it also acts as a steering device for cells in the process of chemotaxis.
Lamellipodin (Lpd) has been shown to be an important component of the lamellipodia and is essential for lamellipodia formation. Thus, Lpd is required for mesenchymal cell migration in two dimensions and neural crest migration in vivo. It localises to the very edge of lamellipodia and functions to recruit Ena/VASP proteins (Ena, Mena, VASP, EVL) to the leading edge of cell. Furthermore, Lpd binds to the Scar/WAVE complex, an actin nucleation promoting factor, which is mediates lamellipodium formation. As demonstrated herein, overexpression of Lpd in cancer cell lines in vitro increases cellular mobility in three dimensions via both Ena/VASP proteins and the Scar/WAVE complex. Lpd promotes metastasis by supporting tumor invasion and intravasation. Furthermore, Lpd appears to be involved in the regulation of cell proliferation. Moreover, two studies with limited patient numbers were not conclusive whether Lpd is overexpressed in breast cancer.
Lamellipodin (Lpd) or RAPH1 (Ras-associated and pleckstrin homology domains-containing protein 1) is required for lamellipodium formation. The lamellipodium is a cytoskeletal protein actin projection on the leading edge of the cell. It contains a quasi-two-dimensional actin mesh, which propels the cell across a substrate. The lamellipodium is born of actin nucleation in the plasma membrane of the cell and is the primary area of actin incorporation or microfilament formation of the cell. Lamellipodia are found primarily in very mobile cells, they are believed to be the actual motor which pulls the cell forward during the process of cell migration. It also acts as a steering device for cells in the process of chemotaxis.
Lpd has been shown to be an important component of the lamellipodia. For example, Lamellipodin (Lpd) helps regulate cell motility and recruits Ena/VASP proteins (Ena, Mena, VASP, EVL) to the leading edge of cell. Overexpression of Lpd in cancer cell lines in vitro has been demonstrated to increase cellular mobility. Conventional wisdom is that Lpd promotes metastasis by supporting tumor invasion and intravasation. However, experimental evidence suggests that Lpd expression does not affect tumor growth. Moreover, multiple studies have suggested that Lpd is not overexpressed in breast cancer.
Because of the crucial role that cellular mobility plays in cancer metastasis, especially breast cancer metastasis, it remains critical to develop assays capable of accurately diagnosing and predicting when cancer cells are or may be at risk of becoming metastatic. Despite the large number of published articles on breast cancer biomarkers, there is a great need for a reliable marker for use in routine clinical practice. Thus, an immediate need exists for the identification of biomarkers with the potential to enhance early diagnosis and to predict patient prognosis, drug resistance development and treatment choice because of high mortality rate due to metastasis.